Project Summary Drug addiction is a major public health issue that has profound medical consequences to individuals, as well as costly social and economic impacts on our society. Unfortunately, treatment options are limited and relapse rates remain high. Unraveling the complex neurobiological changes that contribute to the transition to addiction in vulnerable individuals, therefore, is critical for effective therapeutic development. The cortico-basal ganglia- thalamic (CBGT) network is involved in decision-making, motivation and reward, and alterations within this circuit regulate the development of drug addiction. The prefrontal cortex serves as a key modulator of this circuit, providing strong glutamatergic drive to the striatum, as well as widespread input throughout the CBGT system. Of note, cortical processing is crucial for the patterning of appropriate behavior and loss of top-down cortical control during drug use is thought to play a major role in the transition to addiction, as well as relapse. However, cortical pyramidal neurons can be subdivided into two major types with distinct inputs and projections targets, molecular and receptor profiles, morphologies and electrophysiological characteristics. Cortical neurons that have sparse apical tufts, minimal h-currents, and are regular spiking project bilaterally to striatum and contralateral cortex (Intratelencephalic; IT) whereas cortical neurons that have thick apical tufts, prominent h-currents, and are burst firing send their main axon into the pyramidal tract with collateral projections to ipsilateral striatum and other subcortical structures (Pyramidal Tract; PT). As a result of the distinct connectivity patterns and cellular properties of these two neuronal populations, they are poised to integrate and convey distinct signals for guiding decision-making processes and motivated behaviors. Nonetheless, the role of these two cell populations in the regulation of addiction behaviors has not been examined. The overall goal of this proposal, therefore, is to begin to address this issue by using novel imaging and molecular tools to characterize how IT and PT neurons in PFC regulate drug-context associations, as well as drug-taking and drug-seeking behaviors in rats expressing distinct addiction-risk phenotypes. The guiding hypothesis of this work is that IT and PT neurons in the cortex work in concert to maintain optimal functioning of the CBGT network by regulating aversive and appetitive motivation states, respectively, and dysregulation of these cell types following drug use leads to aberrant signal relays to drugs and associated stimuli that drive compulsive and persistent drug use. This work, therefore, has the potential to uncover novel, cell-type specific processes that contribute to the development of addiction and relapse.